Project Summary This proposal describes a five-year career development program designed to lead the PI to a career as an independent clinician scientist in translational neuroscience, studying mechanisms by which genetic mutations result in abnormal neurodevelopment and epilepsy. Applicant: The applicant holds M.D. and Ph.D. degrees and has completed specialty training in Child Neurology as well as Epilepsy/Clinical Neurophysiology. He has previous experience in neuroscience research using mouse models to study embryonic forebrain development. The career development plan includes a period of mentored research designed to develop the applicant's knowledge in advanced imaging techniques, electrophysiology, transcriptomics, and bioinformatics. This will greatly enhance his existing training and allow him to develop as an independent investigator. The applicant will hone his scientific skills through the proposed research by meetings with his mentor and collaborations with the members of his advisory committee. He will learn research techniques through formal coursework, journal clubs, lab meetings, seminars, and national meetings. The training plan will also include workshops to develop grant writing skills and didactic training in the responsible conduct of research. These opportunities will allow the applicant to develop the conceptual and technical toolbox needed for an independent career in a clinically important field of study. Research Plan: Epilepsy is a major cause of morbidity, mortality, disability, and expense, and affects 470,000 children in the U.S. While many medications to control seizures have been developed, about 30% of patients do not respond to medications, and to date, there are no medications that can prevent or halt the progression of epilepsy. Recently, many genetic causes of epilepsy have been identified, providing insights into pathways involved in epileptogenesis. Mutations causing hyperactivity of the mTOR pathway (so-called ?mTORpathies?) have emerged as an important cause of cerebral malformations and epilepsy, including tuberous sclerosis complex, focal cortical dysplasia, and polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome, which is caused by a homozygous loss-of-function in the STRADA gene. This proposal will test the central hypothesis that loss of STRADA causes cortical malformation and epilepsy by promoting retention of a neural stem cell identity, delaying neuronal differentiation, and increasing synaptic neuronal hyperexcitability. This innovative proposal will use human cortical organoids, 3-D neural structures that resemble the developing cortex, to determine the effect of STRADA mutations on early cortical development (Aim 1), neuronal excitability (Aim 2), and cell-type specific transcriptional changes (Aim 3). This study will provide a platform to develop mechanistically driven therapies that can halt or reverse epileptogenesis for mTORopathies, and our findings should be applicable to epilepsies in a broader context.